T‐cell antigen‐receptor stoichiometry: pre‐clustering for sensitivity

The T‐cell antigen receptor (TCR˙CD3) is a multi‐subunit complex that is responsible for triggering an adaptive immune response. It shows high specificity and sensitivity, while having a low affinity for the ligand. Furthermore, T cells respond to antigen over a wide concentration range. The stoichiometry and architecture of TCR˙CD3 in the membrane have been under intense scrutiny because they might be the key to explaining its paradoxical properties. This review highlights new evidence that TCR˙CD3 is found on intact unstimulated T cells in a monovalent form (one ligand‐binding site per receptor) as well as in several distinct multivalent forms. This is in contrast to the TCR˙CD3 stoichiometries determined by several biochemical means; however, these data can be explained by the effects of different detergents on the integrity of the receptor. Here, we discuss a model in which the multivalent receptors are important for the detection of low concentrations of ligand and therefore confer sensitivity, whereas the co‐expressed monovalent TCR˙CD3s allow a wide dynamic range.